1. Field of the Invention
The invention relates to the application of sequestrants and inhibitors of protease to wounds for the purpose of enhanced healing. The invention also relates to the inclusion of these active agents in wound dressings to which they may be either compositioned or bound by covalent or ionic means for the purpose of controlled release or sequestration.
2. Description of the Prior Art
A wound of the skin is any degradation of its normal structure and function resulting from an internal or external pathology. A healing wound has aspects relating to control of infection, resolution of inflammation, angiogenesis, regeneration of a functional connective tissue matrix, contraction, resurfacing, differentiation, and remodeling. Chronic wounds are wounds that don't heal in a timely process.
Chronic wounds represent a worldwide health problem. Chronic wounds are a growing health care problem largely due to increasing longevity of the American population. Pressure or decubitus ulcers which are a type of chronic wound represent an estimated 3% to 5% incidence in hospital patients. In patients with spinal chord injuries the incidence of chronic wounds is 25% to 85%. Approximately one million Americans hospitalized yearly will develop pressure sores resulting in a cost of 750 million dollars for patient care.
Elastase is perhaps the most destructive enzyme in the body and has been well characterized in non-healing wounds. An excessive concentration of both the serine protease elastase and matrix metalloproteinases (MMPs) in chronic non-healing wounds has been shown to deleteriously degrade cytokine growth factors, fibronectin, and endogenous levels of protease inhibitors necessary for healing. Although numerous studies with both animals and human beings have shown that growth factors may accelerate healing of chronic wounds, therapeutic attempts to modulate the wound healing response with them have had limited success.
The composition of the wound dressing is relevant to designing a mechanism-based approach to protease inhibition in the environment of the wound fluid. (Wiseman D M, Rovee, D T, Alvarez O M Wound dressing: design and use in Wound Healing Biochemical & Clinical Aspects, eds. Cohen I K, Diegelmann, R F, Lindbald, W J, 1992, Hartcourt Brace Jovanovich, Inc. 562-580). The fiber or gel composition of synthetic dressings, applied to chronic wounds, include synthetic hydrogel polymers, collagen, hydrocolloids, alginates and cotton and carboxymethylcellulose. Controlled release of agents linked with important roles in wound healing includes growth factors, antibiotics, and trace elements. The use of the enzyme inhibitor aprotinin for treatment of corneal ulcers was reported, however, there have been no known reports of treatment methods on the release of elastase inhibitors into wounds.
U.S. Pat. No. 5,098,417 to Yamazaki et al. teaches the ionic bonding of physiologically active agents to cellulosic wound dressings.
U.S. Pat. No. 4,453,939 to Zimmerman et al. teaches the inclusion of aprotonin in compositions for “sealing and healing” of wounds.
U.S. Pat. No. 5,807,555 to Bonte et al. teaches the inclusion of inhibitors for alpha-1-protease, collagenase, and elastase in pharmaceutical compositions for promotion of collagen synthesis.
U.S. Pat. No. 5,696,101 to Wu et al. teaches use of oxidized cellulose (e.g. Oxycel) as a bactericide and hemostat in treatment of wounds.
World Patent WO 98/00180 to Watt et al. teaches complexation of oxidized cellulose with structural proteins (e.g. collagen) for chronic wound healing; and references the utility of oligosaccharide fragments produced by the breakdown of oxidized cellulose in vivo in the promotion of wound healing.